Homeostatic Strengthening of Inhibitory Synapses Is Mediated by the Accumulation of GABAA Receptors

Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia 22908, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2011; 31(48):17701-12. DOI: 10.1523/JNEUROSCI.4476-11.2011
Source: PubMed


Mechanisms of homeostatic plasticity scale synaptic strength according to changes in overall activity to maintain stability in neuronal network function. This study investigated mechanisms of GABAergic homeostatic plasticity. Cultured neurons exposed to depolarizing conditions reacted with an increased firing rate (high activity, HA) that normalized to control levels after 48 h of treatment. HA-treated hippocampal neurons displayed an attenuated response to further changes in depolarization, and the firing rate in HA-treated neurons increased above normalized levels when inhibition was partially reduced back to the level of control neurons. The amplitude and frequency of mIPSCs in hippocampal neurons increased after 48 h of HA, and increases in the size of GABA(A) receptor γ2 subunit clusters and presynaptic GAD-65 puncta were observed. Investigation of the time course of inhibitory homeostasis suggested that accumulation of GABA(A) receptors preceded presynaptic increases in GAD-65 puncta size. Interestingly, the size of GABA(A) receptor γ2 subunit clusters that colocalized with GAD-65 were larger at 12 h, coinciding in time with the increase found in mIPSC amplitude. The rate of internalization of GABA(A) receptors, a process involved in regulating the surface expression of inhibitory receptors, was slower in HA-treated neurons. These data also suggest that increased receptor expression was consolidated with presynaptic changes. HA induced an increase in postsynaptic GABA(A) receptors through a decrease in the rate of internalization, leading to larger synaptically localized receptor clusters that increased GABAergic synaptic strength and contributed to the homeostatic stabilization of neuronal firing rate.

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    • "Previous results have reported that the hyperexcitationinduced homeostatic plasticity would result from a synaptic downscaling occurring at both excitatory (Chang et al, 2010; Goold and Nicoll, 2010) and inhibitory synapses (Hartmann et al, 2008; Rannals and Kapur, 2011). Although several mechanisms might be at the basis of such complex event, we concentrated our study on the downregulation of the VGNa þ channel-mediated intrinsic excitability of excitatory "
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    • "The concurrent increase in the density of short-lived boutons suggests increased axonal transport and exchange between neighboring inhibitory synapses, possibly reflecting increased competition for limited (presynaptic) resources (Govindarajan et al., 2011; Ratnayaka et al., 2011). We propose that the rapid adjustment of bouton dynamics and exchange of bouton content along the inhibitory axon during changes in network activity could serve to facilitate presynaptic changes (Hartman et al., 2006; Peng et al., 2010; Rannals and Kapur, 2011; Kuriu et al., 2012). When more presynaptic material would become available over time [e.g. by increased protein synthesis (Huang and Scheiffele, 2008)], an increased demand for presynaptic resources could lead to an overall strengthening of synapses. "
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    • "GABARAPL1 has also been shown to bind to and is potentially implicated in trafficking of the GABAAR (gamma-aminobutyric acid type A receptor) [22]. Regulation of GABAAR numbers and clustering is important for modulation of synaptic strength at inhibitory synapses, which is mediated by an accumulation of the GABAAR at the postsynaptic dendrite to maintain neural network homeostasis [35]. Given that GABARAPL1 interacts with this receptor and is expressed in GABAergic neurons, it may also play a role for in neural network homeostasis. "
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